Polymorphic tandem repeats shape single-cell gene expression across the immune landscape

Tandem repeats (TRs) – highly polymorphic, repetitive sequences dispersed across the human genome – are crucial regulators of gene expression and diverse biological processes. Yet, due to historical challenges in their accurate calling and analysis, TRs have remained underexplored compared to single nucleotide variants (SNVs). Here, we introduce a cell type-specific resource exploring the impact of TR variation on human gene expression. Leveraging whole genome and single-cell RNA sequencing, we catalog over 1.7 million polymorphic TR loci and their associations with gene expression across more than 5 million blood-derived cells from 1,790 individuals. We identify over 58,000 single-cell expression quantitative trait TR loci (sc-eTRs), 16.6% of which are specific to one of 28 distinct immune cell types. Further fine-mapping uncovers 6,210 sc-eTRs as candidate causal drivers of gene expression in 21% of genes tested genome-wide. We show through colocalization that TRs are likely regulators of over 2,000 GWAS loci associated with immune-mediated and hematological traits, and further identify novel TRs warranting investigation in rare disease cohorts. TRs are pivotal, yet long-overlooked, contributors to cell type-specific gene expression, with promising implications for understanding rare disease pathogenesis and the genetic architecture of complex traits.